Over the past ten (10) years, the cost of bringing a drug into the market has increased by 140 percent. Globally, the top twenty (20) pharmaceutical organizations spend nearly sixty (60) billion dollars every year to bring a drug into the market and the average cost is estimated to be $2.6 billion, including drug failures. With the increased demand for rare/life-saving drugs, the Market Authorization Application (MAA) filings are also increasing. A disparity between supply-chain operations and manufacturing processes has led to disconnected systems. Lack of coordination within various departments (clinical science, chemistry, manufacturing, and controls (CMC), nonclinical, pharmacokinetics, pharmacodynamics, medical writing, and clinical operations) has compromised the quality of product information escalating the risk of non-compliance in submissions. Hence, it is essential to understand dossier submissions and the product’s potential value in the marketplace. Pharmaceutical organizations must scrutinize the submission working method via monitoring the timelines and critical path implementation. Let us now take a look at the US - EU submission comparison.

Comparison of Information Submitted

A standard format of how the applicants must submit the data is set up in the files transmitted to the regulators for application submission. Metadata is the fulcrum of all the data required for eCTD submissions. It gives information about other data and is contained in the eCTD backbone files. Metadata is divided into structural metadata, i.e., how data is organized, and descriptive metadata, which provides information about the content.

The US Market

The United States Food and Drug Administration (USFDA) is the first Health Authority to adopt the eCTD format introduced by the International Council for Harmonization (ICH). The applicants need to submit an application form depending on the type of drug proposed, i.e., Investigational New Drug (IND), New Drug Application (NDA), Abbreviated New Drug Application (ANDA), Over-the-Counter Drugs (OTC), Biological License Application (BLA), Drug Master Files (DMFs), etc., along with a cover letter to the USFDA.

The following table explains the details of various submissions and the respective applications in the US:

Submission Type

Submission Sub-Type

Supplement Effective Date Type (If applicable and submission-sub-type “application”)

Valid For Application Types

Original Application

Presubmission

Application

Amendment

Resubmission

 

IND, NDA, ANDA, BLA, DMF, EUA

Efficacy Supplement

Presubmission

 

NDA, BLA

Application

Prior Approval Supplement(PAS)

Amendment

Resubmission

 

Chemistry Manufacturing

Controls Supplement

Presubmission

 

NDA, ANDA, BLA

Application

Prior Approval Supplement (PAS),

Changes Being Effected (CBE-0), or

Changes Being Effected 30 (CBE-30),

Amendment

Resubmission

 

Labeling Supplement

Presubmission

 

NDA, ANDA, BLA

Application

Prior Approval Supplement (PAS), or

Changes Being Effected (CBE-0)

Amendment

Resubmission

 

Annual Report

Report Amendment

 

IND, NDA, ANDA, BLA, DMF

Product Correspondence

Correspondence Amendment

 

IND, NDA, ANDA, BLA, DMF

Postmarketing Requirements or Postmarketing Commitments

Original

Amendment

 

NDA, BLA

Promotional Labeling

Advertising

Original

Resubmission

Amendment

 

NDA, ANDA, BLA

IND Safety Reports

Report Amendment

 

IND

Periodic Safety Reports (Periodic adverse Drug Experience Report (PADER) or periodic safety update report (PSUR)

Report Amendment

 

NDA, ANDA, BLA

Source: www.fda.gov

The most critical element for a successful submission is to have the eCTD modules filled properly and stored in the metadata. The format in which the submissions are to be made is explained as follows:

Module 1 Specifications

The type of submission establishes, defines, and identifies the Regulatory activity. An application can comprise one (01) or more Regulatory activities, each of which can consist of one (01) or more submissions. The first submission of this kind demonstrates the submission ID that will be used in subsequent submissions for the same Regulatory activity in an application. Using the same submission ID number for an activity facilitates submissions to be grouped for that specific activity. This is achieved by using the submission ID number, which is governed by the sequence number of the first submission to each Regulatory activity.

Grouped Submissions

A grouped submission is a single sequence comprising us-regional.xml, index.xml, and any applicable files concerning more than one (01) application. Such a submission terminates the need to submit multiple, identical submissions to different authorities.

Applicants are required to submit all the reports (clinical and non-clinical) for a particular study in modules 4 and 5 in the form of a Study Tagging File (STF) as per the USFDA.

The EU Market

In the EU, applicants need to submit all information in the form of metadata which will be covered as envelope information. Based on the requirement of the applicant, there are four (04) different procedures for the MAA respectively - Centralised Procedure (CP), Decentralised Procedure (DCP), Mutual Recognition Procedure (MRP), and National Procedure (NP).

eCTD Specifications

  • ‘Single’ (variation)
  • ‘Grouping’ (variations of the same type influencing the same marketing authorization)
  • ‘Grouping’ (variations of different types influencing the same marketing authorization)
  • ‘Grouping’ (one (01) or more Type IA variations, influencing multiple marketing authorizations of the same Marketing Authorization Holder (MAH). A high-level submission number is also required for these submissions)
  • ‘Work sharing’ (one (01) or more Type IB and/or Type II variation(s) affecting multiple marketing authorizations of the same MAH. A high-level submission number is also required for these submissions)

Module 4/5

Applicants are not required to re-organize the reports for submission to the European Medicines Agency (EMA) or the National Competent Authority (NCAs). To maintain a compatible eCTD lifecycle and table of contents (via index.xml), applicants are advised to use node extensions for all clinical study reports, regardless of the granularity of the content (i.e., even reports that consist of only one (01) document must also be presented in node extensions).

Conclusion

 

US

EU

Application Submission

Application form + Cover letter

Cover letter + EU eCTD envelope

Information Submission

Applicants are required to submit all the information as reports (clinical and non-clinical) for a particular study in modules 4 and 5 in the form of a Study Tagging File (STF) as per the USFDA.

 

The “EU-envelope” element is designed to be used for all types of submissions (MAAs, variations, renewals, etc.) for a given medicinal product and will mainly be used for the first, simple processing at the Agency level. The envelope provides meta-data at the eCTD application and sequence level.

 

MAA Submission Deadline

Can be submitted anytime

Specific windows, depending on whether your product qualifies for standard review or accelerated.

 

Attainment of high-quality, timely submission that aligns with Regulatory requirements, stakeholders’ interests, and company expectations demands excellent strategic and tactical planning and the focus of a dedicated and experienced Regulatory submissions Project Manager. Based on the Agency requirements, Freyr’s regional experts, with proven capabilities in the Publishing and Submissions (P&S) space, bestow tailor-made services required to meet the application specifications. The experts review each dossier submission, put forth any gaps identified during the review along with the suggestions, and assist in the compilation of the MAA P&S, which includes resubmissions within an industry-leading industry turn-around-time at competitive pricing. Contact Freyr for details.

Author:

Sonal Gadekar
Associate

 

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